Sae 28.8.13

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Sae 28.8.13

  1. 1. Sharpless Epoxidation in Organic Synthesis Dr. Mukund Ghavre 25/09/2013 1 Katsuki ˆ
  2. 2. Why do need selective reactions ?  All kinds of selectivities enrich the art of organic synthesis.  Especially, chemo-selectivity provides an excellent tool to organic chemist for the synthesis of molecules containing a number of functional groups. 25/09/2013 2
  3. 3.  It is the first method for asymmetric epoxidation of allylic alcohols, published on 1st August 1980 in JACS.  Prof. Sharpless says that „it was Katsuki‟s (then his postdoc) idea to use DET for chiral induction‟. 25/09/2013 3
  4. 4.  Works on a wide spectrum of substrates offering > 80 % ee and 70-90 % yield.  5-10 mol% catalyst is required in presence of 3 or 4 Å molecular sieves.  Demands 10-20 mol% excess tartrate wrt Ti catalyst. The stereochemistry of epoxide depends on the enantiomer of tartrate used in reaction. 25/09/2013 4
  5. 5. Ti-Complex 25/09/2013 5 TS proposed by Corey Johnson, R. A.; Sharpless. K. B.; Catalytic Asymmetric Epoxidation of Allylic Alcohols. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I. Ed.; Wiley-VCH: New York, 2000; 231–280; Corey, E. J. J. Org. Chem. 1990, 55, 1693–1694.
  6. 6. 25/09/2013 6
  7. 7. 25/09/2013 7
  8. 8. Choice of tartrate: 25/09/2013 8
  9. 9. 25/09/2013 9 Johnson, R. A.; Sharpless. K. B.; Catalytic Asymmetric Epoxidation of Allylic Alcohols. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I. Ed.; Wiley-VCH: New York, 2000; 231–280; Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 5–26,
  10. 10. Substrate Scope: 25/09/2013 10 Sharpless, K. B.; Behrens, C. H.; Katsuki, T.; Lee, A. W. M.; Marin, S.; Takatani, M.; Viti, S. M.; Walker, F. J.; Woodard S. S. Pure & Appl. Chem. 1983, 55, 589–604. Schweitzer, M. J.; Sharpless, K. B. Tetrahedron Lett. 1985 26, 2543–2546. Gao, Y. Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765–5780. Erickson, T. J. J. Org. Chem. 1986, 51, 934–935.
  11. 11. Choice of Metal: • When allyl alcohol was subjected to SKAE using various metal catalysts, following results were obtained. 25/09/2013 11
  12. 12. Modifications: (A) Molecular Sieves: – Economy – Less catalyst required – Somewhat milder conditions – Ease of isolation – Increased yields – Possible in-situ derivatization 25/09/2013 12
  13. 13. (B) Polymer support: Metal catalyst is mounted on a polymer which makes it (usually) heterogeneous – Lab scale: facilitate workup and isolation – Industry: continuous process – Minimizes catalyst loss during workup – Polymer support vital with water-soluble substrates  Possible Polymers: – alkaloid polymers – polystyrene 25/09/2013 13
  14. 14. 25/09/2013 14  Early work with polystyrene had low % ee  A Scottish group used linear chiral poly (tartrate esters)  Combining benefits of polymer support with the active functionality built in  Reaction gives good yields and % ee  Branched poly(tartrate esters) were found to be even more selective and had higher yields
  15. 15. Kinetic Resolution: 25/09/2013 15Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237–6240. In kinetic resolution, two enantiomers react with different reaction rates in a chemical reaction with a chiral catalyst or reagent, resulting in an enantioriched sample of the less reactive enantiomer.
  16. 16. 25/09/2013 16  Products formed are diastereomeric.  Using the Sharpless mnemonic, contact between the C1 substituent (R) and the catalyst predicts slow reacting isomer. krel = kfast/kslow
  17. 17.  With the exception of Z-disubstituted allylic alcohols, krel > 25.  When krel = 25, the ee of unreacted alcohol is essentially 100% at 60% conversion.  Allylic tertiary alcohols are not successfully epoxidized under Sharpless conditions.  Disubstituted olefin is more reactive than monosubstituted olefin (krel ~100). 25/09/2013 17
  18. 18. 25/09/2013 18Roush J. Org. Chem. 1982, 47, 1371.
  19. 19. Payne Rearrangement 25/09/2013 19Payne J. Org. Chem. 1962, 27, 3819.
  20. 20. 25/09/2013 20 1. In general, the more substituted epoxide is favoured as the reaction product. 2. However, steric factors and relative alcohol acidities (1 > 2 > 3 ) are additional factors which determine the ultimate composition of the equilibrium mixture. 3. The more reactive epoxide can be trapped by strong nucleophiles (e.g., PhSH).
  21. 21. Homoallylic epoxidation: Makita, N.; Hoshino, Y.; Yamamoto, H. Angew. Chem. Int. Ed. 2003, 42, 941–9434.; Blanc, A.; Toste, F. D. Angew. Chem. Int. Ed. 2006, 45, 2096–2099. 25/09/2013 21
  22. 22. Applications in Total Synthesis 25/09/2013 22 Venustatriol Marine-derived natural product discovered initially in 1986, found in red alga Laurencia venusta. Derived in vivo from squalene, made as a triterpene. Shown to have antiviral and anti-inflammatory properties. Structure contains repeated polyether moieties. Key problems: multiple stereocenters and polyether moieties. Corey proposed a “simple and straightforward” disconnection.
  23. 23. 25/09/2013 23 Venustatriol – Retro-synthetic Analysis
  24. 24. Fragment A 25/09/2013 24
  25. 25. Fragment B 25/09/2013 25
  26. 26. 25/09/2013 26 Final step to Venustatriol Corey, E. J.; Ha, D.-C. Tetrahedron Lett. 1988, 29, 3171-3174.
  27. 27. Amphoteronolide - B 25/09/2013 27Nicolaou, K. C.; Daines, R. A.; Chakraborty, T. K.; Ogawa, Y.; J. Am. Chem. Soc., 1988, 110, 4696 – 4705
  28. 28. 25/09/2013 28
  29. 29. (-)-Laulimalide Epoxidation at final stage discriminates between two allylic alcohols to give desired product. 25/09/2013 29
  30. 30. Other Methods for Enantioselective Epoxidation 25/09/2013 30
  31. 31. Chiral Peroxides: • Simplest approach towards asymmetric epoxidation – generally not spectacular. 25/09/2013 31 H-J Hamann et al., Chirality, 1993, 5, 338. A. Lattanzi et al., Chem Comm. 2003, 1440.
  32. 32. Modified Johnson–Corey– Chaykovsky Reaction • Not applicable to broad substrate scopes. Reaction conditions generally clumsy (days or weeks). 25/09/2013 32 N. Furukawa et al. J. Org. Chem., 1989, 54, 4222 P. Metzner et al. J. Org. Chem., 2005, 70, 4166 V.K. Aggarwal and J. Richardson. Chem Comm., 2003, 2644.
  33. 33. Jacobsen Epoxidation • Applicable to most cis-olefins. A small number of conjugated trisubstituted and tetrasubstituted olefins also work (not general). • Also works for electron deficient olefins (enones) but requires higher catalyst loading and longer reaction times. 25/09/2013 33E.N. Jacobsen et al. JACS, 1991, 113, 7063.
  34. 34. Shi Epoxidation: • Useful for epoxidation of trans-disubstituted olefins (ketone 1), trisubstituted olefins (ketone 1), conjugated cis-disubstituted olefins (ketone 2, see p. 3), and styrenes (ketone 2, see p. 3). 25/09/2013 34
  35. 35. Enders Method: • Pros: Oxygen as stoichiometric oxidant. • Cons: Not very broad substrate scope (R2 must be Ph or other large group for good enantioselectivity). 25/09/2013 35D. Enders et al. Angew. Chem. Int. Ed. Eng., 1996, 35, 1725.
  36. 36. Shibasaki Method: • Pros: Catalytic in L-M complex (5 mole %), Broader substrate scope than Enders method. • Cons: Expensive catalyst; mechanism poorly understood (active catalyst is presumed to be oligomeric). 25/09/2013 36M. Shibasaki et al. JACS, 1997, 119, 2329.
  37. 37. Corey Method: • Pros: Catalytic in ligand (0.1 eq.), consistently high e.e. values. • Cons: R2 must be aryl. Ligand is not particularly cheap or easy to come by. Reaction conditions are annoying. 25/09/2013 37E.J. Corey and F-Y Zhang. Org. Lett., 1999, 1(8), 1287 E.J. Corey et al. Tet. Lett., 1996, 37(11), 1735.
  38. 38. Summary: Recommended Methods 25/09/2013 38 Allylic or Terminal Olefins Sharpless Jacobsen HKR Di- or Tri-substituted Olefins Jacobson Shi Shi & Jacobsen Electron Deficient Shibasaki Shibasaki & Jacobsen
  39. 39. How to convert epoxide into olefin ? 25/09/2013 39 "Scott Tips Very Crappy Money; Felipe Counts Nicaraguan Cucumbers." "Scott Tips Very Crappy Money; Felipe Counts Nicaraguan Cucumbers."
  40. 40. THANK YOU ! 25/09/2013 40
  41. 41. 25/09/2013 41 Questions ?

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